The neurodegenerative tauopathies Alzheimer's disease (AD) and Frontotemporal dementia (FTD), are characterized by the intracellular build-up of tau-containing neurofibrillary tangles (NFT), and progressive cognitive dysfunction and neuron death. Studies of the tau/tta-4510 mouse inducible tauopathy model, which closely mimics features of the human diseases, have shown that early accumulation of intermediate-tau species, prior to the formation of NFTs, promote the events leading to neuronal dysfunction and memory loss. miRNAs are a widespread class of small RNAs involved in post-transcriptional regulation, and data from recent studies have illustrated a specific regulatory role for some miRNAs during the neuronal processes involved in learning and memory. This proposed study is designed to test the hypothesis that tau-induced early dysregulation of miRNAs in the tau/tta-4510 model results in the cognitive deficits observed in these mice. The rationale behind this proposed study is based on our exciting pilot data showing multiple miRNAs, including miR-138 (that regulates synapse formation) are dysregulated in tau/tta mice engineered to express the mutant tau transgene and that manifest with cognitive deficits, when compared to age-matched control mice. In addition, many of the dysregulated miRNAs found in the initial pilot study are also abnormally expressed in the human AD brain and are significantly correlated with tangle load. To test our hypothesis, Under Aim 1 we propose to a) Measure miRNA levels in the aged murine tauopathy model via microarrays, utilizing our ability to temporally suppress transgene expression in the model to identify those miRNAs involved in cognition and neurodegeneration rather than those which correlate with NFT accumulation, and b) Compare to datasets of differentially expressed miRNAs in human FTD brains, to c) Identify miRNAs that are concordant between the species and have clinical relevance. Under Aim 2, the miRNAs defined under Aim 1 will be measured temporally during the period that early tau aggregated species begin to accumulate in the murine brain, plus during the onset of cognitive decline (1 month, 2.5 months and 4 months), but prior to extensive neuron loss and tangle formation. We will then use LCM to confirm that temporally dysregulated miRNAs are similarly altered in pre-tangle neurons (PHF1 positive), when compared to controls (PHF1negative). Under Aim 3 we will also identify the functional mRNA targets of the temporally dysregulated miRNAs, using an integrated experimental and computational approach. mRNAs found to be dysregulated in a neuronal cell line, following transfection of Pre-miR or anti-miR oligonucleotides, and also predicted as targets via SEED sequence analysis and assigned functional relevance, will then be validated in the murine tau/tta cortical PHF1 positive and negative neurons as miRNA- regulated targets. PUBLIC HEALTH RELEVANCE: The successful completion of this exploratory study will lead to the identification of clinically relevant miRNAs that are dysregulated during the development of human tauopathy-associated neuropathology and contribute to the cognitive decline seen in human tauopathies such as FTD and AD. We will also identify the mRNA targets of these dysregulated miRNAs. Elucidating the potential role of miRNAs in tauopathy may ultimately allow for the development of medications that can delay, for example, the onset of FTD and AD. Similarly, preventing the diseases and/or their progression, may become a possibility following the successful identification of new targets to prevent miRNA dysregulation and the associated cognitive deficits, and is of exceptional relevance to the mission of the NIH.